The present invention relates to their fields of organic chemistry, biochemistry, medicinal chemistry, microbiology and medicine. In particular, it relates to organic compounds that are fungal efflux pump inhibitors.
The information provided and the references cited herein are not admitted, nor should they be construed, to be prior art to the present invention, but are provided solely to assist the understanding of the reader.
Fungal infections are relatively rare in immuno-competent patients. In fact, a number of Candida species are often present as benign commensal organisms in the digestive system of healthy individuals (Shepherd, et al., Ann. Rev. Microbiol., 1985, 39:579-614). Fungal infections, however, can be life threatening for immuno-compromised patients. Three major groups of immuno-compromised individuals have emerged in recent years: (1) cancer patients undergoing chemotherapy, (2) organ transplant patients being treated with immuno-suppressants, and (3) AIDS patients. Data from the National Nosocomial Infections Surveillance System conducted in the United States showed a 487 percent increase in Candida bloodstream infections between 1980 and 1989 (Rinaldi, et al., Antimicrob. Ag. Chemother., 1995, 39:1-8). Oropharyngeal candidiasis was shown to be the most common fungal infection complication associated with AIDS, studies suggesting that up to 90% of AIDS patients have had at least one episode of the infection (Powderly, AIDS research and Human Retroviruses, 1994, 10:925-929).
There are relatively few clinically useful anti-fungal agents. Among those available to treat serious fungal infection are amphotericin B, flucytosine, fluconazole, itraconazole and ketoconazole (Odds, J. Antimicrob. Chemother., 1993, 31:463-471). A more recent addition to the arsenal of effective compounds is posaconazole. However, resistance to these drugs is developing rapidly. Take, for example, fluconazole.
Fluconazole is currently the most extensively used anti-fungal agent for the treatment of patients with severe candidiasis. It has higher water solubility and a longer plasma half-life than other azoles and has relatively low toxicity. Between 1988 and 1993, fluconazole was used to treat over 15 million patients, including at least 250,000 AIDS patients (Hitchcock, Biochem. Soc. Trans., 1993, 21:1039-1047). Given this wide-spread use, it comes as no surprise that the appearance of fluconazole-resistant Candida strains has been reported (Rex, et al., Antimicrob. Ag. Chemother., 1995, 39:1-8; Vanden Bossche, et al., 1994, supra). In some cases the resistance was found to be due to mutations in C. albicans itself, while in other cases, Candida species less suceptible to fluconazole, such as C. glabrata and C. krusei, replaced C. albicans as the infecting organism (Odds, 1993, supra).
The mechanism of resistance to fluconazole appears to be multifaceted. In one study, amplification of the CYP51 gene (encoding the fluconazole target P-450 protein C14 demethylase) was implicated (Vanden Bossche, et al., Antimicrob. Agents and Chemother., 1994, 36: 2602-2610). In another study, resistance was correlated with the appearance of an altered P-450 target protein with decreased affinity for fluconazole (Hitchcock, Biochem Soc. Trans., 1993, 21:1039-1047). However, fluconazole resistance appears to be primarily related to decreased accumulation of the drug in resistant cells (Vanden Bossche, et al., 1994; Odds, 1993, supra). Species intrinsically resistant to fluconazole, such as C. glabrata, C. krusei and Aspergillus fumigatus, have also been shown to accumulate less fluconazole (Vanden Bossche et al., 1994, supra). C. glabrata and C. krusei, on the other hand, have been shown to accumulate itraconazole and therefore are susceptible to that compound (Marichal et al., Mycoses, 1995, 38:111-117). Thus, it appears that both intrinsic and acquired resistance may be due to decreased drug accumulation in the cell. There are several ways in which a cell can manipulate the concentration of a compound including barring entrance in the first place, decomposition of the compound once it gains access to the interior of the cell or simply excreting the compound before it can have any effect on the cell. This latter approach is called efflux and the cell components that effect efflux, i.e., membrane transporter proteins, are called efflux pumps.
Efflux pumps are ubiquitous in all types of cells, from bacterial to mammalian (Higgins, Ann. Rev. Cell Biol., 1992, 8:67-113). Efflux is driven either by the energy of ATP hydrolysis (ABC-transporter superfamily) or by proton transfer (Major Facilitator superfamily).
Efflux pumps exhibit differing degrees of specificity. Some are extremely specific, such as the TetA efflux pump in gram-negative bacteria, which effluxes tetracycline only. Others are less specific; e.g., the MsrA protein in Staphyloccus aureus effluxes not only erythromycin but related macrolides as well. Then there are efflux pumps that are quite general in their effluxing capability, excreting a variety of structurally unrelated compounds from a cell. Many efflux pumps are clinically significant. For example, resistance to chemotherapeutics in some mammalian cancer cells has been attributed to a P-glycoprotein multi-drug resistant efflux pump (Gottesman, et al., Ann. Rev. Biochem., 1993, 62:385-427). Pseudomonas aeruginosa, the causal agent of respiratory infections, adventitious infection in burn patients, etc., uses Mex efflux pumps to eliminate quinolones, as well as other structurally unrelated antibiotics (Nikaido, Science, 1994, 264:382-388). Multiple-drug resistant (MDR) pumps have been implicated in fluconazole resistance in C. albicans and C. glabrata (Parkinson, et al., Antimicrob. Agents Chemother., 1995, 39:1696-1699; Sanglard, et al., Antimicrob. Agents Chemother., 1995, 39:2378-2386; Albertson, et al., Antimicrob. Agents Chemother., 1996, 40:2835-2841).
What would be useful would be a compound that inhibits the activity of fungal efflux pumps so that anti-fungal agents can accumulate in fungal cells in sufficient quantity to exert their effect. The present invention provides such compounds.
The present invention relates to compounds that are fungal efflux pump inhibitors. When administered, in combination with a therapeutic anti-fungal agent, to a patient suffering from a infection caused by a fungus species that employs efflux pump(s), the compounds inhibit the activity of the pump(s) so that the anti-fungal agent can accumulate in sufficient concentration in the fungal cells to treat the infection.
Thus, in one aspect, the present invention relates to a fungal efflux pump inhibitory compound having the chemical structure: 
wherein:
L1 is selected from the group consisting of a single bond and Cx1;
R1 is selected from the group consisting of:
(C3-C7)heteroalicyclic containing 1 nitrogen atom and 0 to 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur wherein the heteroalicyclic is substituted with one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, xe2x80x94Cx2, xe2x95x90O, xe2x80x94OCx2, xe2x80x94Cx2OCx3, xe2x80x94Cx2OH, xe2x80x94Cx2(halo), xe2x80x94Cx2OC(xe2x95x90O)Cx3, xe2x80x94Cx2NHC(xe2x95x90O)Cx3, xe2x80x94Cx2NHC(xe2x95x90NH)Cx3, xe2x80x94NHCx2, xe2x80x94NCx2Cx3, xe2x80x94Cx2NH2, xe2x80x94Cx2NHCx3, xe2x80x94Cx2NCx3Cx4 and xe2x80x94Cxe2x95x90Cxe2x80x94Cxe2x95x90Cxe2x80x94, wherein the end carbons of the group are covalently bonded to adjacent carbon atoms of the heteroalicyclic ring to form a carbocyclic ring, the adjacent carbon atoms of the heteroalicyclic being double-bonded to one another such that the carbocyclic ring formed is a phenyl group;
xe2x80x94Cx2NHC(xe2x95x90NH)Cx3; xe2x80x94Cx2NCx3C(xe2x95x90NH)Cx13 and,
xe2x80x94Cx2NHC(xe2x95x90O)Cx3;
L2 is selected from the group consisting of xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)NCx5xe2x80x94, xe2x80x94C(S)NHxe2x80x94, xe2x80x94C(S)NCx5xe2x80x94, xe2x80x94C(NH)NHxe2x80x94, xe2x80x94C(NH)NCx5xe2x80x94, xe2x80x94S(O)2NHxe2x80x94; and xe2x80x94S(O)2NCx5xe2x80x94;
R2 is selected from the group consisting of:
aryl substituted with one or more groups independently selected from the group consisting of hydrogen, halo, xe2x80x94Cx6, xe2x80x94Cx6(halo), xe2x80x94Cx6OH, xe2x80x94Cx6OCx7 and xe2x80x94OCx8; and,
Cx8;
R3 is selected from the group consisting of aryl substituted with 1 or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, xe2x80x94Cx9, xe2x80x94OCx9, xe2x80x94NH2, xe2x80x94NHCx9, xe2x80x94NCx9Cx10, xe2x80x94CO2H, xe2x80x94CO2Cx9, xe2x80x94C(O)Cx9, xe2x80x94C(O)NH2, C(O)NHCx9 and C(O)NCx9Cx10;
R4 is selected from the group consisting of Cx11;
R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, halo, xe2x80x94Cx12, xe2x80x94OCx12 and xe2x80x94O(Cx12)Oxe2x80x94; Cx1, Cx2, Cx3, Cx4, Cx5, Cx6, Cx7, Cx8, Cx9, Cx10, Cx11, Cx12 and Cx13 are independently (C1-C4)alkyl; and,
the absolute stereochemistry of centers of asymmetry are independently R or S; or, a pharmaceutically acceptable salt thereof.
As aspect of this invention is a compound wherein L1 is a single bond.
An aspect of this invention is a compound in which R1 is a heteroalicyclic.
An aspect of this invention is the above compound wherein the heteroalicyclic is selected from the group consisting of 
and 
wherein R9 is selected from the group consisting of hydrogen, xe2x80x94Cx2, xe2x80x94Cx2Cl, xe2x80x94Cx2OH and xe2x80x94Cx2OC(O)Cx3.
An aspect of this invention is the above compound wherein the heteroalicyclic is 
An aspect of this invention is the above compound wherein R9 is selected from the group consisting of CH3xe2x80x94, xe2x80x94CH2CH2Cl, xe2x80x94CH2CH2OH and xe2x80x94CH2OC(O)CH3.
An aspect of this invention is the above compound wherein R9 is CH3xe2x80x94.
An aspect of this invention is a compound wherein R2 is phenyl substituted with one or more groups independently selected from the group consisting of hydrogen, halo, xe2x80x94Cx4 and Cx4Oxe2x80x94.
An aspect of this invention is a compound wherein R2 is phenyl optionally substituted with one or more groups independently selected from the group consisting of fluorine, chlorine, CH3 xe2x80x94 and CH3Oxe2x80x94.
An aspect of this invention is a compound wherein L2 is selected from the group consisting of xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)xe2x80x94 and xe2x80x94S(O)2xe2x80x94.
An aspect of this invention is a compound wherein R3 is phenyl substituted with one or more groups independently selected from the group consisting of hydrogen, Cx5xe2x80x94, Cx5Oxe2x80x94 and xe2x80x94O(Cx5)Oxe2x80x94.
An aspect of this invention is a compound wherein R3 is phenyl substituted with one or more groups independently selected from the group consisting of hydrogen, CH3xe2x80x94, CH3Oxe2x80x94 and xe2x80x94OCH2Oxe2x80x94.
An aspect of this invention is a compound wherein R4 is CH3xe2x80x94.
An aspect of this invention is a compound wherein R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, halo, xe2x80x94Cx5 and Cx5Oxe2x80x94.
An aspect of this invention is a compound wherein R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, fluorine and chlorine.
An aspect of this invention is a compound wherein:
L1 is a single bond; and,
R1 is 
wherein R9 is CH3.
An aspect of this invention is a method for inhibiting the growth or proliferation of a fungal cell that employs an efflux pump resistance mechanism, comprising contacting the fungal cell with a anti-fungal agent and a fungal efflux pump inhibitor having the chemical structure: 
wherein:
L1 is selected from the group consisting of a single bond and Cx1;
R1 is selected from the group consisting of:
(C3-C7)heteroalicyclic containing 1 nitrogen atom and 0 to 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur wherein the heteroalicyclic is substituted with one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, xe2x80x94Cx2, xe2x95x90O, xe2x80x94OCx2 , xe2x80x94Cx2OCx3, xe2x80x94Cx2OH, xe2x80x94Cx2(halo), xe2x80x94Cx2OC(xe2x95x90O)Cx3, xe2x80x94Cx2NHC(xe2x95x90O)Cx3, xe2x80x94Cx2NHC(xe2x95x90NH)Cx3, xe2x80x94NHCx2, xe2x80x94NCx2Cx3, xe2x80x94Cx2NH2, xe2x80x94Cx2NHCx3, xe2x80x94Cx2NCx3Cx4 and xe2x80x94Cxe2x95x90Cxe2x80x94Cxe2x95x90Cxe2x80x94, wherein the end carbons of the group are covalently bonded to adjacent carbon atoms of the heteroalicyclic ring to form a carbocyclic ring, the adjacent carbon atoms of the heteroalicyclic being double-bonded to one another such that the carbocyclic ring formed is a phenyl group;
xe2x80x94Cx2NHC(xe2x95x90NH)Cx3; xe2x80x94Cx2NCx3C(xe2x95x90NH)Cx13 and,
xe2x80x94Cx2NHC(xe2x95x90O)Cx3;
L2 is selected from the group consisting of xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)O xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)NCx5xe2x80x94, xe2x80x94C(S)NHxe2x80x94, xe2x80x94C(S)NCx5xe2x80x94, xe2x80x94C(NH)NHxe2x80x94, xe2x80x94C(NH)NCx5xe2x80x94, xe2x80x94S(O)2NHxe2x80x94; and xe2x80x94S(O)2NCx5xe2x80x94;
R2 is selected from the group consisting of:
aryl substituted with one or more groups independently selected from the group consisting of hydrogen, halo, xe2x80x94Cx6, xe2x80x94Cx6(halo), xe2x80x94Cx6OH, xe2x80x94Cx6OCx7 and xe2x80x94OCx8; and,
Cx8;
R3 is selected from the group consisting of aryl substituted with 1 or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, xe2x80x94Cx9, xe2x80x94OCx9, xe2x80x94NH2, xe2x80x94NHCx9, xe2x80x94NCx9Cx10, xe2x80x94CO2H, xe2x80x94CO2Cx9, xe2x80x94C(O)Cx9, xe2x80x94C(O)NH2, C(O)NHCx9 and C(O)NCx9Cx10;
R4 is selected from the group consisting of Cx11;
R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, halo, xe2x80x94Cx12, xe2x80x94OCx12 and xe2x80x94O(Cx12)Oxe2x80x94;
Cx1, Cx2, Cx3, Cx4, Cx5, Cx6, Cx7, Cx8, Cx9, Cx10, Cx11, Cx12 and Cx13 are independently (C1-C4)alkyl; and,
the absolute stereochemistry of centers of asymmetry are independently R or S; or, a pharmaceutically acceptable salt thereof.
In another aspect of this invention the anti-fungal agent is an azole anti-fungal agent.
In another aspect of this invention, the azole anti-fungal agent is selected from the group consisting of fluconazole and posaconazole.
In still another aspect of this invention, a fungal cell is first contacted with an efflux pump inhibitor herein and then contacted with the anti-fungal agent.
In an aspect of this invention, a fungal cell is contacted with the efflux pump inhibitor herein and the anti-fungal agent simultaneously.
In an aspect of this invention, the fungal cell is a genus Candida cell.
In an aspect of this invention, the genus Candida cell is selected from the group consisting of C. albicans, C. krusei, C. tropicalis, C. parapsilosis and C. glabrata. 
In an aspect of this invention, the fungal cell is a genus Aspergillus cell.
In an aspect of this invention the genus Aspergillus cell is an Aspergillus fumigatus cell. 
An aspect of this invention is a method for treating an infection caused by a fungus that employs an efflux pump resistance mechanism, comprising administering to a patient in need thereof a therapeutically effective amount of an anti-fungal agent and an efflux pump inhibitor having the chemical structure: 
wherein:
L1 is selected from the group consisting of a single bond and Cx1;
R1 is selected from the group consisting of:
(C3-C7)heteroalicyclic containing 1 nitrogen atom and 0 to 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur wherein the heteroalicyclic is substituted with one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, xe2x80x94Cx2, xe2x95x90O, xe2x80x94OCx2, xe2x80x94Cx2OCx3, xe2x80x94Cx2OH, xe2x80x94Cx2(halo), xe2x80x94Cx2OC(xe2x95x90O) Cx3, xe2x80x94Cx2NHC(xe2x95x90O)Cx3, xe2x80x94Cx2NHC(xe2x95x90NH)Cx3, xe2x80x94NHCx2, xe2x80x94NCx2Cx3, xe2x80x94Cx2NH2, xe2x80x94Cx2NHCx3, xe2x80x94Cx2NCx3Cx4 and xe2x80x94Cxe2x95x90Cxe2x80x94Cxe2x95x90Cxe2x80x94, wherein the end carbons of the group are covalently bonded to adjacent carbon atoms of the heteroalicyclic ring to form a carbocyclic ring, the adjacent carbon atoms of the heteroalicyclic being double-bonded to one another such that the carbocyclic ring formed is a phenyl group;
Cx2NHC(xe2x95x90NH)Cx3; xe2x80x94Cx2NCx3C(xe2x95x90NH)Cx3 and,
xe2x80x94Cx2NHC(xe2x95x90O)Cx3;
L2 is selected from the group consisting of xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)NCx5xe2x80x94, xe2x80x94C(S)NHxe2x80x94, xe2x80x94C(S)NCx5xe2x80x94, xe2x80x94C(NH)NHxe2x80x94, xe2x80x94C(NH)NCx5xe2x80x94, xe2x80x94S(O)2NHxe2x80x94; and xe2x80x94S(O)2NCx5xe2x80x94;
R2 is selected from the group consisting of:
aryl substituted with one or more groups independently selected from the group consisting of hydrogen, halo, xe2x80x94Cx6, xe2x80x94Cx6(halo), xe2x80x94Cx6OH, xe2x80x94Cx6OCx7 and xe2x80x94OCx8; and,
Cx8;
R3 is selected from the group consisting of aryl substituted with 1 or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, xe2x80x94Cx9, xe2x80x94OCx9, xe2x80x94NH2, xe2x80x94NHCx9, xe2x80x94NCx9Cx10, xe2x80x94CO2H, xe2x80x94CO2Cx9, xe2x80x94C(O)Cx9, xe2x80x94C(O)NH2, C(O)NHCx9 and C(O)NCx9Cx10;
R4 is selected from the group consisting of Cx11;
R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, halo, xe2x80x94Cx12, xe2x80x94OCx12 and xe2x80x94O(Cx12)Oxe2x80x94;
Cx1, Cx2, Cx3, Cx4, Cx5, Cx6, Cx7, Cx8, Cx9, Cx10, Cx11, Cx12 and Cx13 are independently (C1-C4)alkyl; and,
the absolute stereochemistry of centers of asymmetry are independently R or S; or, a pharmaceutically acceptable salt thereof.
It is an aspect of this invention that the infection is caused by a genus Candida fungus.
It is an aspect of this invention that the genus Candida fungus is C. albicans, C. krusei, C. tropicalis, C. parapsilosis or C. glabrata. 
It is an aspect of this invention that the infection is caused by a genus Aspergillus fungus.
It is an aspect of this invention that the genus Aspergillus fungus is Aspergillus fumigatus. 
It is an aspect of this invention that, when treating an infection, the efflux pump inhibitor and the anti-fungal agent are administered to the organism simultaneously.
It is an aspect of this invention that, when treating an infection, the efflux pump inhibitor is administered to the organism followed by administration of the anti-fungal agent.
An aspect of this invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient; and, an efflux pump inhibitor having the chemical structure: 
wherein:
L1 is selected from the group consisting of a single bond and Cx1;
R1 is selected from the group consisting of:
(C3-C7)heteroalicyclic containing 1 nitrogen atom and 0 to 2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur wherein the heteroalicyclic is substituted with one or more substituents independently selected from the group consisting of hydrogen, halo, hydroxy, xe2x80x94Cx2, xe2x95x90O, xe2x80x94OCx2, xe2x80x94Cx2OCx3, xe2x80x94Cx2OH, xe2x80x94Cx2(halo), xe2x80x94Cx2OC(xe2x95x90O)Cx3, xe2x80x94Cx2NHC(xe2x95x90O)Cx3, xe2x80x94Cx2NHC(xe2x95x90NH)Cx3, xe2x80x94NHCx2, xe2x80x94NCx2Cx3, xe2x80x94Cx2NH2, xe2x80x94Cx2NHCx3, xe2x80x94Cx2NCx3Cx4 and xe2x80x94Cxe2x95x90Cxe2x80x94Cxe2x95x90Cxe2x80x94, wherein the end carbons of the group are covalently bonded to adjacent carbon atoms of the heteroalicyclic ring to form a carbocyclic ring, the adjacent carbon atoms of the heteroalicyclic being double-bonded to one another such that the carbocyclic ring formed is a phenyl group;
xe2x80x94Cx2NHC(xe2x95x90NH)Cx3, xe2x80x94Cx2NCx3C(xe2x95x90NH)Cx13 and,
xe2x80x94Cx2NHC(xe2x95x90O)Cx3;
L2 is selected from the group consisting of xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)NCx5xe2x80x94, xe2x80x94C(S)NHxe2x80x94, xe2x80x94C(S)NCx5xe2x80x94, xe2x80x94C(NH)NHxe2x80x94, xe2x80x94C(NH)NCx5xe2x80x94, xe2x80x94S(O)2NHxe2x80x94; and xe2x80x94S(O)2NCx5xe2x80x94;
R2 is selected from the group consisting of:
aryl substituted with one or more groups independently selected from the group consisting of hydrogen, halo, xe2x80x94Cx6, xe2x80x94Cx6(halo), xe2x80x94Cx6OH, xe2x80x94Cx6OCx7 and xe2x80x94OCx8; and,
Cx8;
R3 is selected from the group consisting of aryl substituted with 1 or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, xe2x80x94Cx9, xe2x80x94OCx9, xe2x80x94NH2, xe2x80x94NHCx9, xe2x80x94NCx9Cx10, xe2x80x94CO2H, xe2x80x94CO2Cx9, xe2x80x94C(O)Cx9, xe2x80x94C(O)NH2, C(O)NHCx9 and C(O)NCx9Cx10;
R4 is selected from the group consisting of Cx11;
R5, R6, R7 and R8 are independently selected from the group consisting of hydrogen, halo, xe2x80x94Cx12, xe2x80x94OCx12 and xe2x80x94O(Cx12)Oxe2x80x94;
Cx1, Cx2, Cx3, Cx4, Cx5, Cx6, Cx7, Cx8, Cx9, Cx10, Cx11, Cx12, and Cx13 are independently (C1-C4)alkyl; and,
the absolute stereochemistry of centers of asymmetry are independently R or S; or, a pharmaceutically acceptable salt thereof.
An aspect of this invention is the above composition further comprising a therapeutically effective amount of an anti-fungal agent.
It is an aspect of this invention that the anti-fungal agent is an azole anti-fungal agent.
It is an aspect of this invention that the azole anti-fungal agent is fluconazole or posaconazole.